CA2458524C - C2-disubstituted indane-1-ones and their derivatives, method for their production and their use as medicaments - Google Patents

Abstract

The invention relates to C2-disubstituted indane-1-ones and to their physiologically compatible salts and physiologically functional derivatives. The invention also relates to compounds of formula (I), wherein the groups are defined as per the description, to their physiologically compatible salts and to a method for the production of said compounds. The compounds are suitable for use e.g. as anorexiants.

Description

Description C2-disubstituted indan-1-ones and their derivatives, method for their production and their use as medicamonts The invention relates to C2-disubstituted indan-1-ones and their derivatives and also their physiologically acceptable salts and physiologically functional derivatives.
In F.C. Copp et al., J. Chem. Soc. Perkin I, 1983, 909-914, in the preparation of 2-phenylindan-1-one, 2-phenyl-2-phenylthioindan-1 -one is obtained as an intermediate.

WO 97/20806 discloses cyclopentyl-substituted indan-1-one derivatives having inter alia antiinflammatory action.

WO 98/55439 discloses indan-1-one derivatives which are disubstituted at C2 and have antiinflammatory action.
It was an object of the present invention to provide compounds which cause a reduction in weight in mammals and which are suitable for preventing and treating obesity.

Accordingly, the invention relates to compounds of the formula I
R4 *R!9 R3 x in which R1, R2, R3, R4 independently of one another are H, F, Cl, Br, 1, CN; N3, NO2, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CH2-phenyl, O-phenyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(0)0_2(C1-C8)-alkyl, S(O)0_2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C1-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl; SO3H, S02-NH2, S02-NH-(C1-C8)-alkyl, S02-NH-(C3-C8)-cycloalkyl, NH-SO2-NH2, NH-S02-(C1-C8)-alkyl, NH-S02-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, where in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH3, O-CH2-Ph, NH2, NH-CO-CH3 or N(COOCH2Ph)2;
phenyl, 1- or 2-naphthyl, 5-tetrazolyl, 1-[(C1-C6)-alkyl]-5-tetrazolyl, 2-[(C1-C6)-alkyl]-5-tetrazolyl, 1 -imidazolyl, 1- or 4-[1,2,4]-triazolyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, where the aryl radical or heterocycle may be substituted up to two times by F, Cl, Br, CN, OH, (C1-C4)-alkyl, CF3, O-(C1-C4)-alkyl, S(0)0-2(C1-C6)-alkyl, NH2, NH-S02-(C1-C4)-alkyl, COOH, CO-O-(C1-C4)-alkyl, CO-NH2, and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;

X is S, SO, SO2;

Y is (CH2)p, where p may be 0, 1, 2 or 3;

R5 is CF3, (C1-C1E)-alkyl, (C3-C4)-cycloalkyl, (C6-C8)-cycloalkyl, vvrhere in the alkyl groups one to seven hydrogen atoms can be replaced by fluorine;

(CH2)r-CORE, where r = 1-6 and R6 may be OH, O-(C1-C6)-alkyl or NH2;

CH2-CH(NHR7)-COR8, where R7 may be H or C(O)-(C1-C4)-alkyl and R8 may be OH, O-(C1-C6)-alkyl or NH2;

Phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where the rings or ring systems may be substituted up to two times by F, Cl, Br, I, CN, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0.2(C1-C8)-alkyl, S(O)0_2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl; SO3H, S02-NH2, S02-NH-(C1-C8)-alkyl, SO2-NH-(C3-C6)-cycloalkyl; NH-SO2-NH2, NH-S02-(C1-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;

R9 is F, Cl, Br, CN, CF3, (C,-C18)-alkyl, (C3-C4)-cycloalkyl, (C6-C8)-cycloalkyl, where in the alkyl groups one to seven hydrogen atoms-nay be replaced by fluorine;

(CH2)-CORE, where r = 9-16 and R6 may be OH, 0-(C,-C6)-alkyl or NH2;

CH2-CH(NHR7)-COR8 where R7 may be H or C(O)-(C1-C4)-alkyl and R8 may be OH, O-(C,-C6)-a!kyl or NH2;

(CH2),,-aryl or (CH2)-heteroaryl, where u = 0-6 and aryl may be phenyl, 1- or 2-napthyl, biphenyl or a heterocyclic radical, where the rings or ring systems may be substituted up to two times by F, Cl, Br, I, CN, OH, O(C,-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C,-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0.2(C,-C8)-alkyl, S(O)a2(C3-C8)-cycloalkyl, NH2, NH-(C,-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C,-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl; SO3H, S02-NH2, S02-NH-(C,-C8)-alkyl, S02-NH-(C3-C8)-cycloalkyl; NH-SO2-NH2, NH-S02-(C,-C8)-alkyl, NH-S02-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C,-C8)-alkyl, COOH, CO-OP-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C,-C8)-alkyl, CO-N[(C,-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;

except for the compound of the formula I in which R1, R2, R3 and R4 are hydrogen, X-Y-R5 is S-phenyl and R9 is phenyl, and their physiologically acceptable salts.

Preference is given to compounds of the formula I in which R1, R2, R3, R4 independently of one another are H, F, Cl, Br, CN; N3, NO2, OH, O4C,-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CH2-phenyl, O-phenyl, O-CO-(C,-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, NH2, NH-(C,-C8)-alkyl, N[(C,-C8)-alkyl]2, COOH, CO-O(C,-C8)-alkyl, (C1-C8)-alkyl, (C3-Ca)cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, where in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;

5 phenyl, 1-imidazolyl;
where the aryl radical or heterocycle may be substituted up to two times by F, Cl, Br, CN, OH, (C1-C4)-alkyl, CF3, O-(C1-C4)-alkyl, and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;

X is S, SO, S02;

Y is (CH2)p, where p may be 0, 1, 2 or 3;

R5 is CF3, (C1-C18)-alkyl, where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;

(CH2)r-COR6, where r = 1-6 and R6 may be OH, O-(C1-C6)-alkyl or NH2;

CH2-CH(NHR7)-COR8, where R7 may be H or C(O)-(C1-C4)-alkyl and R8 may be OH, O-(C1-C6)-alkyl or NH2;
Phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where the rings or ring systems may be substituted up to two times by F, Cl, Br, I, CN, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0_2(C1-C8)-alkyl, S(O)0_2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3 C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl; SO3H, SO2-NH2, S02-NH-(C1-C8)-alkyl, S02-NH-(C3-C8)-cycloalkyl; NH-S02-NH2, NH-SO2-(C1-C8)-alkyl, NH-S02-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-OP-C8)-alkyl, COOH, CO-O(C,-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C,-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;

R9 is F, Cl, Br, CN, CF3, (C1-C18)-alkyl, (C3-C4)-cycloalkyl, (C6-C8)-cycloalkyl, where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;
(CH2)u-aryl or (CH2)-heteroaryl, where u = 0-6 and aryl may be phenyl, 1- or 2-napthyl, biphenyl or a heterocyclic radical, where the rings or ring systems may be substituted up to two times by F, Cl, Br, I, CN, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0_2(C1-C8)-alkyl, S(O)0_2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl; SO3H, SO2-NH2, SO2-NH-(C1-C8)-alkyl, S02-NH-(C3-C8)-cycloalkyl; NH-S02-NH2, NH-S02-(C,-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;
except for the compound of the formula I in which R1, R2, R3 and R4 are hydrogen, X-Y-R5 is S-phenyl and R9 is phenyl, and their physiologically acceptable salts.
Particular preference is given to compounds of the formula I in which R1, R2, R3, R4 independently of one another are H, F, Cl, Br, CN; N3, NO2, OH, O(C1-C8)-alkyl, O(C3-CB)-cycloalkyl, O-CH2-phenyl, O-phenyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, N[(C1-C8)-alkyl]2, COOH, CO-O(C1-C8)-alkyl, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, where in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;
phenyl, 1-imidazolyl;

where the aryl radical or heterocycle may be substituted up to two times by F, Cl, Br, CN, OH, (C,-C4)-alkyl, CF3, O-(C,-C4)-alkyl, and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;

X is S, SO2;

Y is (CH2)p, where p may be 0 or 1;
R5 is CF3, (Ci-CB)-alkyl, where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;

phenyl, pyridinyl, where the rings may be substituted up to two times by F, Cl, Br, (C1-C8)-alkyl;

R9 is F, Cl, Br, (C1-C8)-alkyl, where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;

(CH2)õ-phenyl, where phenyl may be substituted up to two times by F, Cl, Br, (CT-C8) alkyl;

except for the compound of the formula I in which R1, R2, R3 and R4 are hydrogen, X-Y-R5 is S-phenyl and R9 is phenyl, and their physiologically acceptable salts.
The invention relates to compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8 and R9 can be straight-chain or branched.

Heterocycle or heterocyclic radical is to be understood as meaning ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. This definition furthermore includes ring systems in which the heterocycle or heterocyclic radical is fused with benzene rings.
Preferred heterocycles or heterocyclic radicals are:

heteroaryls, such as benzimidazolyl, 1-[(C1-C6)-alkyl]benzimidazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, benzoxazolyl, benzothiazolyl, 2-, 3- or 4-pyridyl, pyrimidinyl, 4-, 5- or 6-pyridazin-2H-yl-3-one, 4-, 5- or 6-pyridazin-2-(Cl-C8)-alkyl-2H-yl-3-one, 2-benzyl-4-, -5- or -6-pyridazin-2H-yl-3-one, 3-.or-4-pyridazinyl, 2-, 3-, 4- or 8-quinolinyl, 1-, 3- or 4-isoquinolinyl, i 1-phthalazinyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2-pyrazinyl, 2-quinoxalinyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1-[(C,-C6)-alkyl]-2-, -4- or -5-imidazolyl, 3-, 4- or 5-pyrazolyl, 1-[(C,-C6)-alkyl]-3-, -4- or -5-pyrazolyl, 1- or 4-[1,2,4]-triazolyl, 4- or 5-[1,2,3]-triazolyl, 1-[(C,-C6)-alkyl]-4- or -5-[l ,2,3]triazolyl, 3-, 4- or 7-indolyl, N-[(C,-C6)-alkyl]-3-, -4- or -7-indolyl 2-[(C,-C6)-alkyl]-3(2H)-indazolyl, 1-[(C1-C6)-alkyl]-3(1 H)-indazolyl, 5-tetrazolyl, 1-[(C,-C6)-alkyl]-1 H-tetrazolyl, 2-[(C,-C6)-alkyl]-2H-tetrazolyl.
Pharmaceutically acceptable salts are particularly suitable for medical applica-tions, due to their greater solubility in water compared with the starting or base compounds. Said salts must have a pharmaceutically acceptable anion or cation.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid and also of organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methane-sulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid. For medicinal purposes, particular preference is given to using the chlorine salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

Salts having a pharmaceutically unacceptable anion are likewise included within the scope of the present invention as useful intermediates for preparing or purify-ing pharmaceutically acceptable salts and/or for use in nontherapeutic applica-tions, for example in-vitro applications.
The term "physiologically functional derivative" used herein relates to any physio-logically acceptable derivative of an inventive compound of the formula I, for example an ester which on administration to a mammal, for example humans, is capable of forming (directly or indirectly) a compound of the formula I or an active metabolite thereof.

The physiologically functional derivatives also include prodrugs of the compounds of the invention. Such prodrugs may be metabolized in vivo to a compound of the invention. These prodrugs may or may not be active themselves.
The physiologically functional derivatives furthermore include, for example, glucuronides, sulfuric acid esters, glycosides and ribosides.

The compounds of the invention may also be present in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention are included within the scope of the invention and are another aspect of the invention.

All references to "compound(s) according to formula (I)" refer hereinbelow to a compound/compounds of the formula (I) as described above and also to their salts, solvates and-physiologically functional derivatives as described herein.

The amount of a compound according to formula (I) which is required in order to attain the desired biological effect depends on a number of factors, for example the specific compound selected, the intended use, the type of administration and the clinical state of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg/kg and can be administered in a suitable manner as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individual doses may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampules for injections can contain, for example, from 1 mg to 100 mg, and orally administerable individual dose formulations such as, for example, tablets or capsules can contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the abovementioned masses relate to the mass of the compounds of the structure I on which the salt is based. The compound used for the prophylaxis or therapy of the abovementioned conditions may be the compounds according to formula (I) themselves, but they are preferably present in the form of a pharmaceutical composition together with an acceptable carrier.
The carrier must be naturally acceptable, in the sense that it is compatible with the other ingredients of said composition and is not harmful to the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as an individual dose, for example as a tablet which may contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances may also be present, including further compounds according to formula (I). The pharmaceutical compositions of the invention may be prepared according to any of the known pharmaceutical methods which essentially comprise mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions of the invention are those which are suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable manner of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound according to formula (I) used in each case. Sugar-coated formulations and sugar-coated delayed-release formulations, too, are included within the scope of the invention. Preference is given to acid-resistant and enteric formulations.
Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be present in separate units as, for example, capsules, cachets, lozenges or tablets, which in each case contain a particular amount of the compound according to formula (I);
as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, said compositions can be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may comprise one or more additional components) are contacted. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely dispersed solid carrier, after which the product is shaped, if necessary. Thus a tablet, for example, may be prepared by pressing or shaping a powder or granules of the compound, where appropriate with one or more additional components. Pressed tablets can be prepared by tableting the compound in free-flowing form, for example a powder or granules, mixed, where appropriate, with a binder, lubricant, inert diluent and/or one or more surface active/dispersing agents in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound, moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound according to formula (I) with a flavoring, usually-sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I) which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they may also be administered subcutaneously, intramuscularly or intradermally as an injection.
Said preparations may preferably be prepared by mixing the compound with water and rendering the obtained solution sterile and isotonic with the blood.
Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration are preferably present as individual dose suppositories. These may be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Suitable pharmaceutical compositions for topical application to the skin are preferably present as ointment, cream, lotion, paste, spray, aerosol or oil.
Carriers which may be used are petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. In general, the active compound is present at a concentration of from 0.1 to 15%, for example from 0.5 to 2%, by weight of the composition.

Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal administration may be present as individual patches which are suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active compound in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A
suitable active compound concentration is from approx. 1 % to 35%, preferably approx.
3%
to 15%. A particular possibility is the release of the active compound by electro-transport or iontophoresisas described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

The invention furthermore provides a process for preparing the compounds of the formula I which comprises obtaining the compounds of the formula I by proceeding according to the reaction scheme below:
Formula scheme R4 ~ R4 0 R4 O
R3 halogen R3 4 M' -X-Y-R5 R3 4 R9 I Hal X
RZ e.g. Br2 R2 / % R2 Y-RS

II III I (X = S) base I RS-Y-X-X-Y-RS
e.g.
fluorination or CI-X-Y-RS
or alkylation oxidation I
or oxidation III Z
reaction with an (and subsequent fluorination aldehyde and subsequent or ailrylation) reduction R3 R3 9 oxidation II R3 8 R9 I Y ..-- I X
Rp R2 -R5 RZ Y-RS

IV I (X = S02) I (X = SO) e.g. bromination and subsequent reaction with M=-X-Y-R5.

To this end, compounds of the formula II, RI
Formula II

in which R1, R2, R3 and R4 are as defined above are converted with a halogen, such as, for example, bromine or chlorine, into a compound of the formula III.
The compounds- of-the formula III are converted further with metal salts of thiols of the formula H-X-Y-R5, where X is sulfur and Y and R5 are as defined above into compounds of the formula I where X = S and R9 = H. These metal salts can be employed as such or they can be generated in solution in situ from the thiol and a base, such as, for example, aqueous sodium hydroxide.
On the other hand, compounds of the formula I where X = S and R9 = H can be obtained by reacting compounds of the formula II with a base, such as, for 5 example, lithium diisopropylamide, for example in tetrahydrofuran, and with a disulfide of the formula R5-Y-X-X-Y-R5 in which R5 and Y are as defined above and X = S; alternatively, instead of the disulfide, it is also possible to use a sulfenyl chloride of the formula CI-X-Y-R5 where X = S and Y and R5 are as defined above (see, for example, D. Seebach et al.; Chem. Ber. 109, 1601-1616 (1976)).
Compounds of the formula I in which X = S and R9 is not hydrogen can be obtained, for example, as follows: compounds of the formula II are subjected, for example, to a fluorination, alkylation or a condensation with an aldehyde and subsequent reduction, giving compounds of the formula IV which for their part can be converted, for example after bromination with compounds of the formula M+-X-Y-R5, where X = S and Y and R5 are as. defined above, to compounds of the formula I where X = S and R9 is not hydrogen.

Compounds of the formula I in which X = SO and R9 is not hydrogen can be prepared for example, by selective oxidation of the compound of the formula I
in which X = S, using one equivalent of peroxytrifluoroacetic acid (C. G. Venier et al.;
J. Org. Chem. 47, 3773 (1982)). The preparation of the sulfoxides from the sulfides can also be carried out using manganese dioxide or chromic acid (D.
Edwards et al.; J. Chem. Soc. 1954, 3272). Furthermore suitable for this oxidation is hydrogen peroxide in acetic anhydride (A. V. Sviridova et al.; J. Org. Chem (Russ), English Transl.; 7, 2577 (1971)).

Compounds of the formula I in which X = SO2 and R9 is not hydrogen can be obtained by oxidation using, for example, 2KHSO5 x KHSO4 x K2SO4 (Oxone), either from compounds of the formula I in which X = S and R9 is not hydrogen or from compounds of the formula I in which X = SO and R9 is not hydrogen (see, for example, M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186, American Chemical Society, Washington, DC, 1990).

Compounds of the formula I in which X = S, SO or SO2 and R9 is not hydrogen, for example is phenyl, and Y is a bond and R5 is as described above can also be obtained by reacting compounds of the formula I in which X = S-phenyl and R9 = H and Y is a bond and R5 is as described above with, for example, diphenyliodonium chloride. The resulting compounds can either be converted stepwise into the corresponding compounds in which X = SO or S02, or they are subsequently desulfurized with zinc/acetic acid and are then available for further reactions according to the scheme above.
Compounds of the formula I in which X = SO or S02, R9 = H and Y = a bond (= (CH2)m where m = 0) can also, alternatively, be prepared according to the scheme below (shown for the preparation of the aryl sulfoxides (H. J. Monteiro et al.; Tetrahedron Letters 11, 921-924 (1975) and aryl sulfones (A. K. Maiti et al.;
Tetrahedron 50, 10483-10490 (1994)):

R3 * Ar,,S=0 R3 R9 R2 base R2 / Ar II
I (X = SO; Y = bond) R4 O O Na R4 O
R3::[(: Ar,,S=0 R3 R9 R2 R2 Ar RI RI
11 I (X = SO=; Y = bond) Compounds of the formula I in which X = SO2 and R9 is not hydrogen and Y and R5 are as defined above can also be obtained by subjecting compounds of the formula I in which X = SO2 and R9 = H and Y and R5 are as defined above to a fluorination or alkylation, for example.

Inorganic acids suitable for forming salts are, for example: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic acid.

Organic acids suitable for salt formation which may be mentioned are, for example: formic acid, acetic acic, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, isethionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 1,2-benzisothiazol-3(2H)-one, 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.

The examples shown below serve to illustrate the invention without limiting it. The melting points or decomposition points (m.p.) measured are uncorrected and generally depend on the heating rate.
The retention times given in the table below refer to the following methods for determination:

Method A: Column: Merck, LiChroCart 55-2, PuroSpher STAR, RP 18 e;
measured at 254 nm; gradient: solvent A acetonitrile/water 90:10 + 0.5% formic acid; solvent B acetonitrile/water 10:90 + 0.5 % formic acid; flow rate: 0.750 ml/min; time (min)/solvent B (%): 0.00/95.0, 0.50/95.0, 1.75/5.0, 4.25/5.0, 4.50/95.0, 5.00/95.0; temperature: 40 C:

Method B: column: YMC J'sphere, 33x2, ODS H 80 4 N; measured at 254 nm;
gradient: solvent A acetonitrile + 0.5% formic acid; solvent B water + 0.5%
formic acid; flow rate: 1.00 ml/min; time (min)/solvent B (%): 0.00/90.0, 2.50/5.0, 3.30/5.0, 3.35190.0; temperature: 30 C:

Table 1: Examples X

RI
Formula I

Exam R1 R2 R3 R4 X Y R5 R9 m.p.[ C]
ple [MH+]
2 H CI H H SO2 - CH3 CH2Ph 335.2 3 H OCH3 OCH3 H SO2 - CH3 F 289.2 Retention time in min (method A or B) 4 H CI H H S Pyridin-2-yl F 2.789 (A) H Cl H H S CH2 CF3 F 2.699 (B) 6 H H H H S - C6H4-4-CI F 3.096 (A) 7 H CI H H SO2 - Pyridin-2-yl F 1.460 (B) 8 H CI H H SO2 CH2 CF3 F 1.514 (B) 9 H C6H4- H H SO2 - CH3 F 2.628 4-CI (B) H CF3 H H SO2 - CH3 F 2.261 (B) 11 H H C6H4-4- H SO2 - CH3 F 2.656 CF3 (B) 12 Br H H H SO2 - CH3 F 2.182 (B) 13 H N- H H SO2 - CH3 F 2.221 (B) phthalim idoyl The compounds of the formula I are distinguished by beneficial actions on the metabolism of lipids, and they are particularly suitable for weight reduction and, after weight reduction, for maintaining a reduced weight in mammals and as anorectic agents. The compounds are distinguished by their low toxicity and their few side effects. The compounds may be employed alone or in combination with other weight-reducing or anorectic active compounds. Further anorectic active compounds of this kind are mentioned, for example, in the Rote Liste 2001, Rote Liste Service GmbH, Frankfurt/Main, Chapter 01 under weight-reducing agents/appetite suppressants, and may also include those active compounds which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of said organism such that increased calorie intake does not cause an enlargement of the fat depots and a normal calorie intake causes a reduction in the fat depots of said organism. The compounds are suitable for the prophylaxis and, in particular, for the treatment of problems of excess weight or obesity.
The compounds are furthermore suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, of arteriosclerosis and for the normalization of lipid metabolism and for the treatment of high blood pressure.

In a further aspect of the invention, the compounds of the formula I may be administered in combination with one or more further pharmacologically active substances which may be selected, for example, from the group consisting of antidiabetics, antiadipose agents, blood-pressure-lowering active compounds, lipid reducers and active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2 derivatives such as, for example, those disclosed by Novo Nordisk A/S in WO 98/08871 and also oral hypoglycemic active compounds.

Said oral hypoglycemic active compounds preferably include sulfonyl ureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed by Novo Nordisk A/S in WO
5 97/26265 and WO 99/03861, insulin sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example glycogen phosphorylase inhibitors, modulators of glucose uptake and glucose elimination, lipid metabolism-modifying compounds such as antihyperlipidemic active compounds and antilipidemic active compounds, 10 for example HMGCoA-reductase inhibitors, inhibitors of cholesterol transport/cholesterol uptake, inhibitors of the reabsorption of bile acid or inhibitors of microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and PXR agonists and active compounds which act on the ATP-dependent potassium channel of beta cells.

15 In one embodiment of the present invention, the present compounds are administered in combination with insulin.

In another embodiment, the compounds of the invention are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide.

20 In another embodiment, the compounds of the present invention are administered in combination with a biguanide such as, for example, metformin.

In another embodiment, the compounds of the present invention are administered in combination with a meglitinide such as, for example, repaglinide.

In yet another embodiment, the compounds of the present invention are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed by Dr. Reddy-s Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

in yet another embodiment, the compounds of the present invention are administered in combination with a monoamine oxidase inhibitor such as disclosed, for example, in WO 01/12176. Particularly suitable for this purpose are [3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1 H-oxazolo[3,4-a]quinolin-1-one, (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-one or (R)-5-(methoxymethyl)-3-[6-cycl o p ro pylmeth oxybe nzofu ra n-3-yl]oxazol id i n-2-o n e.

In another embodiment, the compounds of the present invention are administered in combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose.

In yet another embodiment, the present compounds are administered in combination with an hCNTF (human ciliary neurotrophic factor) or derivatives thereof, such as, for example, CNTFAx15 or modified CNTFAX15, such as disclosed, for example, in Lambert et al., PNAS 98, 4652-4657.

In another embodiment, the compounds of the present invention are administered in combination with an active compound which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.

In yet another embodiment, the compounds of the present invention are administered in combination with an antihyperlipidemic active compound or an antilipidemic active compound such as, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.

In another embodiment, the compounds of the present invention are administered in combination with more than one of the aforementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin-insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

Furthermore, the compounds of the invention may be administered in combination with one or more antiadipose agents or appetite-controlling active compounds.
Such active compounds may be selected from the group consisting of CART
agonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4) agonists, melanin-concentrating hormone (MCH) antagonists, orexin antagonists, H3 agonists, TNF
agonists, CRF agonists, CRF BP antagonists, urocortin agonists, 03 adrenoceptor agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenalin reuptake inhibitors, 5HT modulators, bombesin agonists, galanin antagonists, glucocorticoid receptor modulators, growth hormone, growth-hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin receptor agonists, leptin mimetics, dopamine agonists (bromocriptine, doprexin), lipase/amylase inhibitors, cannabinoid receptor 1 antagonists, modulators of acylation-stimulating protein (ASP), PPAR
modulators, RXR modulators or TR-P agonists.

In one embodiment of the invention, the antiadipose agent is leptin or modified leptin.

In another embodiment, the antiadipose agent is dexamphetamine or amphetamine.

In another embodiment, the antiadipose agent is fenfluramine or dexfenfluramine.
In yet another embodiment, the antiadipose agent is sibutramine or the mono-and bis-demethylated active metabolite of sibutramine.

In another embodiment, the antiadipose agent is orlistate.

In another embodiment, the antiadipose agent is mazindol, diethylpropione or phentermine.

Furthermore, the compounds of the present invention may be administered in combination with one or more anti hypertensive active compounds. Examples of antihypertensive active compounds are betablockers such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and also aiphablockers such as doxazosin, urapidil, prazosin and terazosin.
Furthermore, reference may be made to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, 1995.

It is self-evident that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be regarded as covered by the scope of protection of the present invention.

The activity of the compounds of the formula I was assayed as follows:
Biological test model:

The anorectic action was tested on female NMRI mice. After removal of feed for 24 hours, the preparation to be tested was administered intraperitoneally (ip) or by gavage (po). The animals were housed singly and, with free access to drinking water, they were offered evaporated milk 30 minutes after administration of the preparation. The consumption of evaporated milk was determined and the general behavior of the animals was monitored every half an hour for 7 hours. The measured milk consumption was compared to that of vehicle-treated control animals.

Table 2: Anorectic action, measured as a reduction in the cumulative milk consumption by treated animals compared with control animals Compound Dose Number of Number of Reduction in /Example animals/ animals/ cumulative milk [mg/kg]
cumulative milk cumulative milk consumption as R3 R4 consumption consumption % of the control X I / R9 Y-RS by treated by untreated R7 animals control animals Formula I N / [ml] N / [ml]

Example 1 20 5/2.00 5/3.86 48 The table indicates that the compounds of the formula I exhibit very good anorectic action.
The preparation of some examples is described in detail below; the other compounds of the formula I were obtained analogously:

Example 1: 5-Chloro-2- fluoro-2-methanesulfonylindan-1-one:
1. 5-Chloro-2-methylsulfanylindan-1 -one:

0.98 g (4 mmol) of 2-bromo-5-chloroindan-1 -one and 0.42 g (6 mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treated in an ultrasonic bath for 30 minutes and then stirred at room temperature for 90 minutes. The reaction mixture is concentrated under reduced pressure and chromatographed on silica gel using toluene/ethyl acetate 10/1. The eluates are concentrated under reduced pressure, giving 0.63 g of 5-chloro-2-methylsulfanylindan-1 -one of melting point 90 C.
2. 5-Chloro-2-methanesulfonylindan-1-one:

0.5 g (2.35 mmol) of 5-chloro-2-methylsulfanylindan-1 -one is dissolved in 10 ml of methanol; at 0 C, a solution of 4.33 g (7.05 mmol) of 2KHSO5 X
KHSO4 x K2SO4 in 10 ml of water is added dropwise. The mixture is stirred at room temperature for 5 h; the methanol is distilled off and the aqueous 5 residue is extracted with dichloromethane. The organic phase is separated off, dried over MgSO4, filtered and concentrated under reduced pressure.
This gives 0.5 g of 5-chloro-2-methanesulfonylindan-1 -one of melting point 197 C.

10 3. 5-Chloro-2-fluoro-2-methanesulfonylindan-1 -one:

0.734 g (3 mmol) of 5-chloro-2-methanesulfonylindan-1-one and 1.77 g (5 mmol) of N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) are suspended in a mixture of 2.5 ml of water and 15 7.5 ml of acetonitrile and stirred under reflux for 4 h. The reaction mixture is cooled, concentrated under reduced pressure and purified chromatographically on silica gel using the mobile phase dichloromethane.
This gives 5-chloro-2-fluoro-2-methanesulfonylindan-1-one of melting point 150 C.
Example 2: 2-Benzyl-5-chloro-2-methanesulfonylindan-1 -one:

1. Methyl 2-benzyl-5-chloro-1-oxoindane-2-carboxylate:

1.11 ml of diisopropylamine are dissolved in 25 ml of dry tetrahydrofuran, 6.9 ml of N-butyllithium in n-hexane (15%) are added at -50 C, and the mixture is stirred at -10 C for 20 minutes. At -50 C, 2.25 g of methyl 5-chloro-1-oxoindane-2-carboxylate, dissolved in 25 ml of tetrahydrofuran, are then added dropwise. The mixture is stirred at -50 C for 30 min, and a solution of 1.31 ml of benzyl bromide in 5 ml of tetrahydrofuran is then added dropwise.
The reaction mixture is stirred at room temperature for 20 h. To bring the reaction to completion, another 1.31 ml of benzyl bromide are added and the mixture is heated under reflux for 72 h. 20 ml of saturated sodium bicarbonate solution are added to the reaction mixture, which is then diluted with ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives methyl 2-benzyl-5-chloro-1-oxoindane-2-carboxylate having a molecular weight of 314 (C18H15C103); MS
(ESI): 315.1 (MH+).

2. 2-Benzyl-5-chloroindan-1 -one:

The compound of example 2.1 is suspended in a mixture of 10 ml of ethanol and 10 ml of 5% strength aqueous sodium hydroxide solution and stirred at 40 C for one hour. The alcohol is then removed under reduced pressure and the residue is extracted with ethyl acetate. The organic phase is washed with water until neutral, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified chromatographically on silica gel using n-heptanelethyl acetate 2/1. This gives 2-benzyl-5-chloroindan-1-one having a molecular weight of 256 (C16H13CIO); MS (ESI):
256.8 (MH+).

3. 2-Benzyl-2-bromo-5-chloroindan-1 -one:

0.86 g of the compound of example 2.2 is dissolved in 4 ml of acetic acid, 50 gi of 48% strength HBr solution and 0.207 ml of bromine are added and the mixture is stirred at room temperature for one hour.
The crude product is purified chromatographically on silica gel using toluene. This gives 2-benzyl-2-bromo-5-chloroindan-1 -one having a molecular weight of 334 (C16H12BrClO); MS (ESI): 334.8 (MH+).

4. 2-Benzyl-5-chloro-2-methanesulfonylindan-1-one:

I mmol of the compound of example 2.3 and 1.2 mmol of methanesulfinic acid sodium salt in 3 ml of dimethylformamide are stirred at 70 C for 4 hours. The crude product is purified chromatographically on silica gel using n-heptane/ethyl acetate 1/1.
This gives 2-benzyl-5-chloro-2-methanesulfonylindan-1 -one of molecular weight 334 (C17H15Cl03S); MS (ESI): 335.2 (MH+).

The compounds of examples 4-6 are obtained by reacting the corresponding 2-fluroindan-1-one with the sodium salt of the corresponding mercaptan.

The compounds of examples 7-13 are obtained as described in example 1.3 by fluorination of the corresponding sulfonyl derivatives.

Claims (10)

Claims:

1. A compound of the formula I, in which R1, R2, R3, R4 independently of one another are H, F, Cl, Br, I, CN, N3, NO2, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CH2-phenyl, O-phenyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0-2(C1-C8)-alkyl, S(O)0-2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C1-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl, SO3H, SO2-NH2, SO2-NH-(C1-C8)-alkyl, SO2-NH-(C3-C8)-cycloalkyl, NH-SO2-NH2, NH-SO2-(C1-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)alkyl]2, (C1-C8)-alkyl, (C3-C8)cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, where in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine, or one hydrogen is optionally replaced by OH, OC(O)CH3, O-CH2Ph, NH2, NH-CO-CH3 or N(COOCH2Ph)2, phenyl, 1- or 2-naphthyl, 5-tetrazolyl, 1-[(C1-C6-alkyl]-5-tetrazolyl, 2-[(C1-C6)-alkyl]-5-tetrazolyl, 1-imidazolyl, 1- or 4-[1,2,4]-triazolyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, where the aryl radical or heterocycle is optionally substituted up to two times by F, Cl, Br, CN, OH, (C1-C4)-alkyl, CF3, O-(C1-C4)-alkyl, S(O)0-2(C1-C6)-alkyl, NH2, NH-SO2-(C1-C4)-alkyl, COOH, CO-O-(C1-C4)-alkyl, CO-NH2, and where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
X is S, SO, SO2;
Y is (CH2)p, where p is 0, 1, 2 or 3;
R5 is CF3, (C1-C18)-alkyl, (C3-C4)-cycloalkyl, (C6-C8)-cycloalkyl, where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
(CH2)r-COR6, where r = 1-6 and R6 is OH, O-(C1-C6)-alkyl or NH2;
CH2-CH(NHR7)-COR8, where R7 is H or C(O)-(C1-C4)-alkyl and R8 is OH, O-(C1-C6)-alkyl or NH2;
Phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where the rings or ring systems are optionally substituted up to two times by F, Cl, Br, I, ON, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0-2(C1-C4)-alkyl, S(O)0-2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl, SO3H, SO2-NH2, SO2-NH-(C1-C8)-alkyl, SO2-NH-(C3-C8)-cycloalkyl, NH-SO2-NH2, NH-SO2-(C1-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine;
R9 is F, Cl, Br, CN, CF3, (C1-C18)-alkyl, (C3-C4)-cycloalkyl, (C6-C8)-cycloalkyl, where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
(CH2)r-COR6, where r = 9-16 and R6 is OH, O-(C1-C6)-alkyl or NH2;

CH2-CH(NHR7)-COR8 where R7 is H or C(O)-(C1-C4)-alkyl and R8 is OH, O-(C1-C6)-alkyl or NH2, (CH2)u-aryl or (CH2)u-heteroaryl, where u = 0-6 and aryl is phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where the rings or ring systems are optionally substituted up to two times by F, Cl, Br, I, ON, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0-2(C1-C8)-alkyl, S(O)0-2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl, SO3H, SO2-NH2, SO2-NH-(C1-C8)-alkyl, SO2-NH-(C3-C8)-cycloalkyl, NH-SO2-NH2, NH-SO2-(C1-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine;
except for the compound of the formula I in which R1, R2, R3 and R4 are hydrogen, X-Y-R5 is S-phenyl and R9 is phenyl, and its physiologically acceptable salts

2. A compound of the formula I as claimed in claim 1, characterized in that R1, R2, R3, R4 independently of one another are H, F, Cl, Br, ON, N3, NO2, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CH2-phenyl, O-phenyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, N[(C1-C8)-alkyl]2, COOH, CO-O(C1-C8)-alkyl, (C1-C8)-alkyl, (C3-C8)cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, where in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine, phenyl, 1-imidazolyl, where the aryl radical or heterocycle is optionally substituted up to two times by F, Cl, Br, CN, OH, (C1-C8)-alkyl, CF3, O-(C1-C4)-alkyl, and where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
X is S, SO, SO2;

Y is (CH2)p, where p is 0, 1, 2 or 3;
R5 is CF3, (C1-C18)-alkyl, where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
(CH2)r-COR6, where r = 1-6 and R6 is OH, O-(C1-C6)-alkyl or NH2;
CH2-CH(NHR7)-COR8, where R7 is H or C(O)-(C1-C4)-alkyl and R8 is OH, O-(C1-C6)-alkyl or NH2;
Phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where the rings or ring systems are optionally substituted up to two times by F, Cl, Br, I, CN, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0-2(C1-C8)-alkyl, S(O)0-2(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C8)-alkyl, NH-CO-(C3-C8)-cycloalkyl, SO3H, SO2-NH2, SO2-NH-(C1-C8)-alkyl, SO2-NH-(C3-C8)-cycloalkyl, NH-SO2-NH2, NH-SO2-(C1-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C8)-cycloalkyl, CO-NH2, CO-NH(C1-C8)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine;
R9 is F, Cl, Br, CN, CF3, (C1-C18)-alkyl, (C3-C4)-cycloalkyl, (C6-C8)-cycloalkyl, where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
(CH2)u-aryl or (CH2)u-heteroaryl, where u = 0-6 and aryl is phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where the rings or ring systems are optionally substituted up to two times by F, Cl, Br, I, CN, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, S(O)0-2(C1-C8)-alkyl, S(O)0-2(C3-C8)-cycloalkyl, NH2, NH-(C1-C6)-alkyl, NH-(C3-C8)-cycloalkyl, N[(C1-C8)-alkyl]2, N[(C3-C8)-cycloalkyl]2, NH-CO-(C2-C6)-alkyl, NH-CO-(C3-C8)-cycloalkyl, SO3H, SO2-NH2, SO2-NH-(C1-C8)-alkyl, SO2-NH-(C3-C8)-cycloalkyl, NH-S02-NH2, NH-SO2-(C1-C8)-alkyl, NH-SO2-(C3-C8)-cycloalkyl, O-CH2-COOH, O-CH2-CO-O(C1-C8)-alkyl, COOH, CO-O(C1-C8)-alkyl, CO-O-(C3-C6)-cycloalkyl, CO-NH2, CO-NH(C1-C6)-alkyl, CO-N[(C1-C8)-alkyl]2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine;

except for the compound of the formula I in which R1, R2, R3 and R4 are hydrogen, X-Y-R5 is S-phenyl and R9 is phenyl, and its physiologically acceptable salts.

3. A compound of the formula I as claimed in claim 1 or 2, characterized in that R1, R2, R3, R4 independently of one another are H, F, Cl, Br, CN, N3, NO2, OH, O(C1-C8)-alkyl, O(C3-C8)-cycloalkyl, O-CH2-phenyl, O-phenyl, O-CO-(C1-C8)-alkyl, O-CO-(C3-C8)-cycloalkyl, NH2, NH-(C1-C8)-alkyl, N[(C1-C8)-alkyl]2, COOH, CO-O(C1-C8)-alkyl, (C1-C8)-alkyl, (C3-C8)cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, where in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms are optionally replaced by fluorine, phenyl, 1-imidazolyl, where the aryl radical or heterocycle is optionally substituted up to two times by F, Cl, Br, CN, OH, (C1-C4)-alkyl, CF3, O-(C1-C4)-alkyl, and where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
X is S, SO2, Y is (CH2)p, where p is 0 or 1, R5 is CF3, (C1-C8)-alkyl, where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
phenyl, pyridinyl, where the rings are optionally substituted up to two times by F, Cl, Br, (C1-C8)-alkyl, R9 is F, Cl, Br, (C1-C8)-alkyl, where in the alkyl groups one to seven hydrogen atoms are optionally replaced by fluorine;
(CH2)u-phenyl, where phenyl is optionally substituted up to two times by F, Cl, Br, (C1-C8)-alkyl;
except for the compound of the formula I in which R1, R2, R3 and R4 are hydrogen, X-Y-R5 is S-phenyl and R9 is phenyl, and its physiologically acceptable salts.

4. A pharmaceutical composition comprising one or more compounds as claimed in any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

5. A compound as claimed in any one of claims 1 to 3 for use as a medicament for reducing weight in mammals.

6 A compound as claimed in any one of claims 1 to 3 for use as a medicament for the prophylaxis or treatment of obesity.

7. A compound as claimed in any one of claims 1 to 3 for use as a medicament for the prophylaxis or treatment of type II diabetes.

8. The use of the compounds as claimed in any one of claims 1 to 3 for preparing a medicament for the prophylaxis or treatment of obesity.

9. The use of the compound as claimed in any one of claims 1 to 3 for preparing a medicament for the prophylaxis or treatment of type II diabetes.

10. A process for preparing the compounds as claimed in claim 1, characterized in that, according to the formula scheme below a compound of the formula II is reacted via a compound of the formula IV in which R9 is different from hydrogen and in which the radicals are as defined for formula I
with a sulfur compound of the formula M+ -X-Y-R5 to give a compound of the formula I where X
= S and R9 is not hydrogen; and compounds of the formula I in which X = S and R9 is different from hydrogen are reacted with oxidizing agents to give compounds of the formula I
in which X=
SO or SO2 and R9 is different from hydrogen; and compounds of the formula II
where R9 =
H are converted into compounds of the formula I in which Y is a bond and X=SO
or SO2 and R9 is H, and the resulting compounds of the formula I in which X=SO2 and R9 is H are further converted into compounds in which R9 is not H and has the meanings given above.